F1012‐2 inhibits the growth of triple negative breast cancer through induction of cell cycle arrest, apoptosis, and autophagy

Abstract

Sesquiterpene lactones (SLs) are plant-derived constituents that have been proved to have potential antitumour activity. However, the intracellular molecular targets of SLs and the underlying molecular mechanisms have not been well elucidated. Here, we report that F1012-2, a novel SL active fraction, isolated from Eupatorium lindleyanum DC., can significantly inhibit the growth of triple-negative breast cancer (TNBC) cells (MDA-MB-231 and MDA-MB-468) but has no obvious inhibitory effect on the growth of human mammary epithelial cells (MCF-10A). The related mechanisms on cell growth inhibition of F1012-2 were demonstrated by inducing apoptosis in a caspase-dependent manner through the intrinsic pathway and extrinsic pathway. F1012-2 could also activate autophagy in TNBC cells. Simultaneously, we found that F1012-2-induced apoptosis was enhanced by inhibition of autophagy. Furthermore, F1012-2 could induce cell cycle arrest at G2/M phase with decreasing expression of cyclin B1, cdc2, and upregulating p21, p-cdc2. Also, F1012-2 activated Akt and p38 signalling pathways. In vivo, F1012-2 exhibited a potential antitumour effect in MDA-MB-231 xenografts without apparent toxicity. Taken together, our results identified that F1012-2 inhibited cell growth via multiple signalling pathways in vitro and in vivo. These data suggest that F1012-2 may be a potential natural active fraction for the treatment of TNBC.

The multifaceted role of autophagy in cancer and the microenvironment

“…An example hereof is the treatment of a triple‐negative breast cancer cell line with a plant‐derived anticancer drug that induced apoptosis and activated autophagy. Here, inhibition of autophagy with 3‐MA served to augment the level of apoptotic cell death . Similarly, in colorectal cancer cell lines, a proapoptotic polyamine analog simultaneously induced apoptosis and autophagy, with 3‐MA cotreatment enhancing induction of apoptotic cell death .…”

Eupalinolide J induces apoptosis, cell cycle arrest, mitochondrial membrane potential disruption and DNA damage in human prostate cancer cells

“…(Compositae) is a traditional Chinese medicine, which has been widely used to treat cough and tracheitis (Yang et al, 2007). A variety of biological activities of this herb have been identified, including anti-inflammatory (Wang et al, 2018b), anti-cancer (Tian et al, 2018;Yang et al, 2019Yang et al, , 2016 and anti-oxidant (Yan et al, 2011) activities. Eupalinolide J (EJ), one of the main compounds in this plant, is a novel sesquiterpene lactone isolated in our lab.…”

Targeting pharmacophore with probe‐reactivity‐guided fractionation to precisely identify electrophilic sesquiterpenes and its activity of anti‐TNBC

“…Moreover, thiol/disulphide homeostasis was reported to play a critical role in antioxidant defence and detoxification in the body . Thus, through Michel's reaction, ESs with specific electrophilic groups alkylate the enzymes or transcription factors, regulate key cellular signal pathways, and then produce anti‐TNBC activity . Targeted covalent modification has emerged as a validated approach to drug discovery with the recent US Food and Drug Administration (FDA) approvals of afatanib (2013), ibrutinib (2013), and osimertinib (2015) drugs that were designed to undergo an irreversible hetero‐Michael addition reaction with a unique cysteine residue of a specific protein …”

“…14 Thus, through Michel's reaction, ESs with specific electrophilic groups alkylate the enzymes or transcription factors, 15,16 regulate key cellular signal pathways, and then produce anti-TNBC activity. 7,8,13,[17][18][19][20] Targeted covalent modification has emerged as a validated approach to drug discovery with the recent US Food and Drug Administration (FDA) approvals of afatanib (2013), ibrutinib (2013), and osimertinib (2015) drugs that were designed to undergo an irreversible hetero-Michael addition reaction with a unique cysteine residue of a specific protein. 21 The bioassay-guided fractionation seems to have succeeded greatly for the discovery of new drug candidates during the past century.…”